Optimization of ether and aniline based inhibitors of lactate dehydrogenase

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

“…Several scaffolds with potent LDHA inhibition have been developed by pharmaceutical companies, including AstraZeneca (compound 33 ), GlaxoSmithKline ( GSK 2837808A ), and Genentech ( GNE-140 ) (Figure ). Upon examining the SAR and the crystal structures of these compounds bound to LDHA, we were intrigued by the class of pyrazole-based LDHA inhibitors and their unique binding conformation . The nanomolar inhibitor compound 63 (Figure B) highlights three key interactions: (1) thiazole acid warhead with residue Arg168 and Thr247, (2) cyclopropyl π–π interaction with Tyr238 (not shown for clarity), and (3) sulfonamide with Asp140, Glu191, and Ile141.…”

“…After an S N Ar reaction with 1-(3-sulfanylphenyl)­ethanone, the sulfur-linked triazole carboxylate 3 , was synthesized. The acetyl group of 3 allowed further construction of the compound 63 -like scaffold, following literature procedures . The acetophenone 3 underwent a magnesium bromide-catalyzed soft enolization in the presence of Hünig’s base, yielding 1,3-diketone 4 in 51% yield, which was then alkylated with 4-(bromomethyl)-2-fluorobenzenesulfonamide.…”